Use of glucosamine, chondroitin, and omega-3 fatty acid supplements in relation to inflammation and risk of colorectal cancer

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In a prior exploratory analysis conducted within the VITamins and Lifestyle (VITAL) cohort study, we observed that use of glucosamine, chondroitin, and omega-3 polyunsaturated fatty acid (omega-3 PUFA)-containing fish oil supplements was associated with decreased risk of colorectal cancer (CRC) after 5 years of follow-up. With an additional 2 years of follow-up in the VITAL cohort, we have examined these associations in more detail among 77,719 adults aged 50-76, and have explored the biologic mechanisms by which these supplements may reduce CRC risk. Data on 220 VITAL biomarker study participants was used to test whether use of glucosamine, chondroitin, and fish oil supplements is associated with oxidative stress, DNA damage, and DNA repair capacity. Additionally, we have used data from the National Health And Nutrition Examination Survey (NHANES) to evaluate the association between use of these supplements and inflammation among 9,947 adults aged 25 and older. Persons reporting use of glucosamine+chondroitin on 4+ days/week for 3+ years had 45% lower risk of CRC than non-users [Hazard Ratio (HR): 0.55; 95% CI: 0.30-1.01; p-trend: 0.16]. This association varied by body mass index (p-interaction: 0.006), with a significant inverse association observed among the overweight/obese only. As compared to non-use, high use of fish oil supplements (4+ days/week for 3+ years) was associated 49% reduced of CRC (HR: 0.51; 95% CI: 0.26-1.00; p-trend: 0.06). The association between fish oil use and decreased risk of CRC was primarily observed among men (p-interaction: 0.02), and for cancers of the colon rather than cancers of the rectum (p-difference: 0.05). We also examined the associations between omega-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and CRC, as well as between dark fish consumption and CRC. While total (diet+supplementary) EPA+DHA intake and dark fish consumption were not associated with CRC overall, these associations were modified by underlying genetic risk (p-interaction: 0.009 and 0.02, respectively): significant inverse associations were observed among persons of low and moderate genetic risk, while positive associations were observed among persons of high genetic risk. Glucosamine and chondroitin supplements were also observed to be associated with reduced oxidative stress, as measured by prostaglandin 2 alpha (p-trend: 0.01 and p-trend: 0.003, respectively) and reduced inflammation, as measured by high-sensitivity C-reactive protein (hsCRP). Persons reporting use of glucosamine supplements experienced 17% lower hsCRP than non-users (0.83; 95% CI: 0.74-0.93), while chondroitin users had 22% lower hsCRP than non-users (0.78; 95% CI: 0.67-0.92). However, use of glucosamine and chondroitin supplements was not associated with DNA damage, DNA repair, or 8-isoprostane, another measure of oxidative stress. Fish oil supplement use was associated with reduced hsCRP (ratio: 0.84; 95% CI: 0.71-1.00), but not with measures of oxidative stress/DNA damage. Our findings suggest that use of glucosamine, chondroitin, and fish oil supplements may be associated with a reduced risk of CRC and offer plausible biologic mechanisms to support these observed associations. CRC poses a substantial health burden in the United States, and there is great need to identify safe and effective preventives. Further research will be needed to better understand the chemopreventive potential of these supplements.